! Alzheimer?s disease (AD) is a neurodegenerative disorder that deprives patients of their cognitive faculties and their memories. In addition to being the fifth leading cause of death in the United States, current estimates suggest that the annual global costs associated with AD could soon exceed one trillion dollars. Nevertheless, despite considerable effort, existing therapeutic strategies targeting AD are highly limited in both number and efficacy, suggesting that novel approaches for preventing or treating AD are needed. Recent human genetic studies have identified a small number of AD susceptibility genes, which might be new drug targets for AD. At the top of this new list of AD-associated genes are members of the Membrane Spanning 4a (Ms4a) gene family. Dozens of large-scale human genetic studies comparing individuals with AD to people without AD, have revealed that mutations in Ms4a genes are amongst the most strongly and reproducibly linked genetic abnormalities that lead to altered susceptibility to AD. However, the physiological function of MS4A proteins, and how Ms4a gene mutations alter susceptibility to AD are not known. I recently uncovered the first clear function of MS4A proteins (Greer et al., Cell, 2016). I found that Ms4a genes encode a novel family of chemoreceptors, proteins that detect extracellular small molecules and relay the presence of those molecules to the cells in which they are expressed. Intriguingly, I have also recently discovered that MS4A receptors are expressed in microglia, the resident immune cells of the nervous system. While the specific role of microglia in AD is the subject of active debate, it is now widely accepted that these cells play a crucial role in AD, and thus the finding that Ms4as are expressed within these cells is of great interest. We have further discovered that Ms4a genes are not expressed in all microglia; rather, the expression of Ms4a genes and proteins is restricted to a previously undescribed subpopulation of microglia, which represents approximately 5% of all microglia in the central nervous system. An analysis of the other genes expressed by this subpopulation of microglia has revealed that a majority of the other AD-associated risk factor genes are either exclusively expressed, or highly enriched for their expression, within this novel population of microglia. These findings, and others described in detail within this proposal, have led me to hypothesize that MS4A chemoreceptor function within this novel population of cells is critical for AD pathogenesis. My goal in this proposal is to test this hypothesis by characterizing this new population of microglia, by elucidating the biological role of MS4A proteins within these cells, and by exploring how Ms4a gene mutations lead to increased risk of AD. Together these approaches represents an exciting and innovative new direction in AD research. These experiments will both enhance our basic understanding of microglial biology and provide insight into how Ms4a mutations contribute to AD. Importantly, as MS4A receptors are potentially highly druggable targets, these experiments could lead to a new therapeutic approach for treating or preventing AD.